Abstract Over the past decade, disparate infectious and non-infectious diseases ranging from cancer and autoimmunity to bacterial and viral infections have been tied together through the common involvement of sugar moieties. For many years adaptive immunology has maintained a model in which peptides are the only specific antigens that are presented via the major histocompatibility complexes to T cells, and are therefore required components for vaccine and immunotherapeutic applications. In the last several years, I have demonstrated that at least one class of carbohydrates can also be presented by MHC molecules, thus shifting the long- standing "peptide only" paradigm of MHC presentation. This work was the subject of an article published in Cell and leads to my hypothesis that glycans are capable of inducing clonal expansion of a specific T cell subset that recognizes MHCII/glycan complexes. I propose to create the first glycan-MHC tetramer and to use this reagent to determine if clonal expansion of carbohydrate-reactive T cells occurs. If successful, the findings would re-define the current T cell recognition paradigm to include carbohydrates as specific MHCII-dependent stimulators of adaptive immunity, thus opening the door to new immunotherapeutic possibilities. Construction of a glycoantigen/MHC tetramer will also open up the power of the tetramer technique (the original report with peptide antigens has been cited 1877 times to date) to the study of the glycome and utilize the enormous advances that are occurring in our understanding of cell glycans to enable identification of glycan-induced immune responses. As such, I believe this proposal represents the ideal combination of attributes suitable for the DP2 funding mechanism (Section 05: Immunology) through the Office of the Director since our findings could hold profound implications for human health across traditional institute barriers through the creation of vaccines and/or immunotherapeutics targeting specific carbohydrate epitopes in the treatment of cancer, autoimmunity and a host of infectious diseases.